EP0699197B1 - 4-p-fluorbenzoyl-1-piperidinyl-propoxy-chromen-4-on derivate, deren herstellung und deren verwendung zur behandlung von psychosen und schizophrenie - Google Patents

4-p-fluorbenzoyl-1-piperidinyl-propoxy-chromen-4-on derivate, deren herstellung und deren verwendung zur behandlung von psychosen und schizophrenie Download PDF

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Publication number
EP0699197B1
EP0699197B1 EP95913143A EP95913143A EP0699197B1 EP 0699197 B1 EP0699197 B1 EP 0699197B1 EP 95913143 A EP95913143 A EP 95913143A EP 95913143 A EP95913143 A EP 95913143A EP 0699197 B1 EP0699197 B1 EP 0699197B1
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EP
European Patent Office
Prior art keywords
och
chromen
fluorobenzoyl
piper
propoxy
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Expired - Lifetime
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EP95913143A
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English (en)
French (fr)
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EP0699197A1 (de
Inventor
Rafael Foguet
Jordi Bolos
Aurelio Sacristan
José A. ORTIZ
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Ferrer Internacional SA
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Ferrer Internacional SA
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Priority claimed from ES09400581A external-priority patent/ES2101620B1/es
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present invention relates to new chromene compounds having the general formula (I): wherein R 1 and R 2 are hydrogen, alkyl having from 1 to 4 carbon atoms, halogen, trifluoromethyl, phenyl, or hydroxymethyl, as well as their pharmaceutically acceptable addtion salts.
  • hydrochloride is preferred.
  • Acetonitrile is appropriate as a nonpolar solvent, and as a base it is useful to employ an alkali metal carbonate or hydrogen carbonate.
  • Potassium iodide can be used as a catalyst.
  • the reaction occurs under heating, preferably at the boiling temperature of the mixture.
  • Intermediate (II) can be purchased from commercial source. This reaction can be illustrated according to Scheme 1.
  • the intermediates of the general formula (III) wherein X is chlorine, bromine or iodine and R 1 and R 2 are hydrogen, alkyl having from 1 to 4 carbon atoms, halogen, trifluoromethyl, phenyl, may be prepared, although not in a limitative manner, a) by alkylation of the corresponding 7-hydroxy-chromen-4-ones of general formula (IV) wherein R 1 and R 2 are as defined in (I) with 1-bromo-3-halopropane of general formula (V) wherein X is as defined in (III), or b) by cyclization from the corresponding 4-(3-halopropoxy)-2-hydroxyacetophenones of general formula (VI) wherein X is as defined in the preceding structure, all of this according to Scheme 2.
  • [Y] is a halogenating agent which is able to introduce a chlorine, bromine or iodine atom, such as tert -butyl hypochlorite, chlorine, bromine or iodine.
  • a chlorine, bromine or iodine atom such as tert -butyl hypochlorite, chlorine, bromine or iodine.
  • the intermediates of the general formula (III) wherein X is chlorine, bromine or iodine, R 1 is hydrogen and R 2 is hydroxymethyl may be prepared through two steps from the 4'-(halopropoxy)-2'-hydroxy-acetophenones of general formula (VI) by alkylation in dimethylformamide with phosphoryl chloride followed by addition on ice and subsequent reduction of the so-formed 7-(3-halopropoxy)-3-formyl-chromen-4-ones of general formula (IX) wherein X is as defined in the preceding structures with sodium borohydride according to conventional procedures of organic chemistry as shown in Scheme 2'.
  • the raw material required for performing the reactions shown in these schemes may be obtained either from commercial sources or according to conventional procedures of organic chemistry.
  • EP Patent No. 546389 discloses substituted piperidyl-methyl chromanes as dopamine and serotonin receptor inhibitors which are potentially useful for treating CNS diseases, such as anxiety, depression, psychosis, Alzheimer's disease, etc.
  • EP Patent No. 441506 discloses 3-piperidino-4-hydroxy-chromanes that can be used in the treatment of CNS diseases, such as stroke, Alzheimer's disease, Parkinson's disease and Huntington's disease.
  • PCT Patent application No. 9012795 discloses substituted chromanes that are potentially useful for treating CNS diseases, such as aggressive behaviour, delirium and confusion, and impotence.
  • 8702359 discloses aminoalcohols from the family of dihydrobenzothiophene and thiochromane having antihypertensive, antithrombotic, hypolipidemic, spasmolytic, calcium antagonist and neuroleptic actions.
  • US Patent No. 4678787 discloses 4H-1-benzopyran-4-ones and their analogs containing sulfur, which are potentially useful to treat psychosis and schizophrenia.
  • US Patent No. 4617314 discloses dihydrobenzofuranyl- and benzopyranyl-carboxamides having antidopamine, antiemetic and methamphetamine potentiating actions.
  • EP-A-0 190 015 and J. Med. Chem. (1991), 34(1), P. 248-256 disclose 4H-1-benzopyran-4-ones and their sulfur containing analogues which are said to be efficient for the treatment of psychosis including schizophrenia.
  • WO-A-91 18597 and J. Med. Chem. (1992), 35(9), p. 1526-1535 disclose compounds of the formula wherein A1, A2, A3, X, Y, and Z have specified meanings. The compounds are said to be useful to inhibit ⁇ binding site-induced activity.
  • EP-A-0 064 255 discloses compounds which are 4-benzamidopiperidin-1-ylalkoxychromen-4-one derivatives which exhibit anti-allergenic, anti-anaphylactic activities.
  • WO-A-90 06921 discloses inter alia compounds which are arylpiperidin-1-yl-1-alkoxychromen-4-one derivatives which show anti-thrombotic, anti-atherosclerotic activities.
  • EP-A-0 558 245 discloses compounds which are 4-arylpiperidin-1-yl-alkoxychromen-4-one derivatives which show hypertensive activities.
  • the compounds of formula (I) are different from the compounds disclosed in the aforesaid patents and prove not to be obvious in view of the prior art described in these patents.
  • the compounds exhibit an interesting profile as neuroleptics as evidenced by both biochemical and pharmacological data.
  • the biochemical tests revealed an intense action of these compounds on various receptors that are generally considered to be involved in the neuroleptic action ( ⁇ , D 2 5HT 2 receptors, B.L. Largent et al: "Eur. J. Pharmacol.”, 155 , 345-7, 1988; 5HT 1a receptors, B.A. McMillen et al: "Drug Dev.
  • the compounds of this invention are characterized by a genuine neuroleptic profile, since advantageously their specificity over 5HT 2 receptors versus D 2 receptors according to D 2 /5HT 2 ratios is higher than that of haloperidol.
  • the specificity of the compound of Ex. 1 over ⁇ receptors versus D 2 receptors is also higher than that of haloperidol and surpasses BMY-14802 and risperidone in D 2 /5HT 2 ratio.
  • the compound is active on D 3 receptors in the same order as 7-OH-DPAT. All this confers potentially valuable properties on the compounds of this invention as neuroleptics, which are useful in psychosis and schizophrenia, and no extrapyramidal effects are attributed to their interaction with D 2 receptors.
  • the neuroleptic activity of the compounds of this invention was confirmed in Animal Pharmacology by oral testing of the inhibition of p -chloro-amphetamine-induced hyperactivity (T.G. Heffner et al: "J.Pharmacol.Exp.Ther.”, 251 , 105, 1989), inhibition of apomorphine-induced hyperactivity (A. Puech et al: “Eur.J.Pharmacol.”, 50 , 291-300, 1978) and inhibition of apomorphine-induced climbing behaviour (P.Protais et al: "Psychopharmacology", 50 , 1-6, 1976).
  • mice Male Swiss mice weighing 22-26 g were used. One week prior to experiment, animals were kept in our facilities at a temperature of 20-22°C and 12/12 h light-dark cycle, and had free access to food and water.
  • the device consists of a top transparent cage for placing of animals and a lower command panel for starting and calibration of it, as well as a system for animal activity detection.
  • mice Male Swiss mice weighing 22-26 g were used. One week prior to experiment, animals were kept in our facilities at a temperature of 20-22°C and 12/12 h light-dark cycle, and had free access to food and water.
  • the device consists of a top transparent cage for placing of animals and a lower command panel for starting and calibration of it, as well as a system for animal activity detection.
  • mice Male Swiss mice weighing 22-26 g were used. One week prior to experiment, animals were kept in our facilities at a temperature of 20-22°C and 12/12 h light-dark cycle, and had free access to food and water. Two hours prior to experiment, the animals were placed in individual cages without access to food.
  • each animal was placed on the bottom of a small upright box (7.5x4.5 cm).
  • the walls of the box were made of translucent methacrylate except one of the lateral surfaces (7.5 cm wide) which was a 3-mm wire mesh.
  • the compounds of this invention are found to be potentially useful as neuroleptics for treating psychosis and schizophrenia.
  • the compound of Example 1 7-[3-(4- p -fluorobenzoyl-1-piperidinyl)propoxy]-chromen-4-one hydrochloride
  • the compound of Example 3 7-[3-(4- p -fluorobenzoyl-1-piperidinyl)propoxy]-3-methyl-chromen-4-one hydrochloride
  • the compound of Example 4 3-Hydroxymethyl-7-[3-(4- p -fluorobenzoyl-1-piperidinyl)propoxy]chromen-4-one hydrochloride, are preferred.
  • the compound of Example 1 was biochemically the most specific over 5HT 2 receptors versus D 2 receptors.
  • the compound of Example 3 was very active in animal pharmacological tests and, moreover, its extrapyramidal effects were not very important; the oral administration of this compound to rats at a dose of 50 mg/kg (over 10 times ED 50 - Test C) caused catalepsy in only 60% of treated animals 3 hours after administration and inhibited stereotypy in only 23% of animals.
  • the compound of Example 4 was also very active in animal pharmacological tests and did not show very important extrapyramidal effects either; in effect, in rat oral testing, it was necessary to administer a dose of 15 mg/kg of product so that catalepsy could occur in 50% of treated animals.
  • IR (KBr): 3200-3600, 2930, 2300-2800, 2680. 1650, 1630, 1595, 1445, 1270, 1230 cm -1 .
  • IR (KBr): 3200-3600, 2300-2800, 1680, 1650, 1630, 1595, 1445, 1270, 1230 cm -1 .
  • composition for 1 ampoule 7-[3-(4- p -Fluorobenzoyl-1-piperidinyl)propoxy] chromen-4-one hydrochloride 5.0 mg Methyl p -hydroxybenzoate 1.0 mg Propyl p -hydroxybenzoate 0.1 mg Bidistilled water to volume 2.0 ml
  • composition for 10 mg tablet 7-[3-(4- p -Fluorobenzoyl-1-piperidinyl)propoxy] chromen-4-one hydrochloride 10.0 mg Corn starch 43.2 mg Talc 6.0 mg Hydrogenated castor oil 2.0 mg Lactose to volume 200.0 mg
  • composition for 50 mg tablet 7-[3-(4- p -Fluorobenzoyl-1-piperidinyl)propoxy] chromen-4-one hydrochloride 50.0 mg Corn starch 86.4 mg Talc 12.0 mg Hydrogenated castor oil 4.0 mg Lactose to volume 400.0 mg

Claims (6)

  1. Chromen-Verbindungen der Formel (I):
    Figure 00370001
    worin R1 und R2 für Wasserstoff, Alkyl mit 1 bis 4 Kohlenstoffatomen, Halogen, Trifluormethyl, Phenyl oder Hydroxyethyl stehen, sowie pharmazeutisch akzeptable Additionssalze davon.
  2. Verbindungen nach Anspruch 1, nämlich:
    7-[3-(4-p-Fluorbenzoyl-1-piperidinyl)propoxy]-chromen-4-on;
    7-[3-(4-p-Fluorbenzoyl-1-piperidinyl)propoxy]-3-methyl-chromen-4-on;
    3-Hydroxymethyl-7-[3-(4-p-Fluorbenzoyl-1-piperidinyl)propoxy]-chromen-4-on
    und pharmazeutisch akzeptable Additionssalze davon.
  3. Chromen-Verbindungen der Formel (I) nach Anspruch 1 oder 2 zur Verwendung bei der Behandlung von Psychose und Schizophrenie.
  4. Pharmazeutische Zusammensetzung, die wenigstens eine Verbindung der Ansprüche 1 oder 2 gegebenenfalls in Kombination mit pharmazeutisch akzeptablen Trägern und/oder Adjuvantien umfaßt.
  5. Verwendung einer Verbindung nach Anspruch 1 oder 2 zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung eines von Psychose und Schizophrenie betroffenen Säugers.
  6. Verfahren zur Herstellung der Chromen-Verbindungen der Ansprüche 1 oder 2, wobei man 4-(p-Fluorbenzoyl)piperidin der Formel II
    Figure 00380001
    alkyliert mit einem 7-(3-Halopropoxy)chromen-4-on der Formel III
    Figure 00380002
    worin X Chlor, Brom oder Jod ist, und R1 und R2 wie in Anspruch 1 definiert sind, und gewünschtenfalls eine Verbindung der Formel I in Form der freien Base in ein Säureadditionssalz überführt.
EP95913143A 1994-03-18 1995-03-17 4-p-fluorbenzoyl-1-piperidinyl-propoxy-chromen-4-on derivate, deren herstellung und deren verwendung zur behandlung von psychosen und schizophrenie Expired - Lifetime EP0699197B1 (de)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
ES09400581A ES2101620B1 (es) 1994-03-18 1994-03-18 Nuevo compuesto derivado del cromeno.
ES9400581 1994-03-18
ES09401437A ES2101635B1 (es) 1994-03-18 1994-07-01 Nuevo compuesto derivado del cromeno
ES9401437 1994-07-01
ES09500163A ES2101644B1 (es) 1994-03-18 1995-01-30 Nuevo compuesto derivado del cromeno
ES9500163 1995-01-30
PCT/EP1995/001008 WO1995025733A1 (en) 1994-03-18 1995-03-17 4-p-fluorobenzoyl-1-piperidinyl-propoxy-chromen-4-one derivatives, their preparation and their use in the treatment of psychosis and schizophrenia

Publications (2)

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EP0699197A1 EP0699197A1 (de) 1996-03-06
EP0699197B1 true EP0699197B1 (de) 2000-06-07

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US (1) US5643927A (de)
EP (1) EP0699197B1 (de)
JP (1) JP3170287B2 (de)
AT (1) ATE193705T1 (de)
AU (1) AU683549B2 (de)
CA (1) CA2163251A1 (de)
DE (1) DE69517371T2 (de)
DK (1) DK0699197T3 (de)
FI (1) FI955386A0 (de)
GR (1) GR3034226T3 (de)
IL (1) IL112764A0 (de)
NO (1) NO308001B1 (de)
NZ (1) NZ282810A (de)
PH (1) PH31442A (de)
PT (1) PT699197E (de)
WO (1) WO1995025733A1 (de)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL117646A (en) * 1995-04-12 2000-06-01 Ferrer Int 7-¬3-¬4-(6-fluoro-1,2-benzisoxazole-3-YL)piperidin-1-YL¾propoxy¾3-alkyl-chromen-4-ones their preparation their uses and pharmaceutical compositions comprising them
ES2144355B1 (es) * 1997-12-30 2001-01-01 Ferrer Int Compuestos derivados del cromeno.
ES2154176B1 (es) * 1998-09-21 2001-10-16 Ferrer Int Nuevo procedimiento de obtencion de 3-(hidroximetil)cromen-4-onas.
WO2002069973A1 (en) * 2001-03-02 2002-09-12 Sepracor, Inc. Piperidine-piperazine ligand for neurotransmitter receptors
US7504395B2 (en) 2001-07-20 2009-03-17 Psychogenics, Inc. Treatment for attention-deficit hyperactivity disorder
JP5380069B2 (ja) * 2005-03-11 2014-01-08 ハワード フローリー インスティチュート フラボノイド化合物およびその使用
EP1829873A1 (de) 2006-03-02 2007-09-05 Laboratorios Del Dr. Esteve, S.A. Pyrrazolderivate als Sigma-Rezeptoren-Antagonisten

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3576810A (en) * 1968-06-20 1971-04-27 Robins Co Inc A H 1-substituted-3-(-4)-aroylpiperidines
DE3117389A1 (de) * 1981-05-02 1982-11-18 Boehringer Mannheim Gmbh, 6800 Mannheim Benzopyranylether, verfahren zu deren herstellung sowie diese verbindungen enthaltende arzneimittel
US4678787A (en) * 1985-01-30 1987-07-07 Warner-Lambert Company 4H-1-benzopyran-4-ones and their sulfur containing analogs
DK623586A (da) * 1985-12-27 1987-06-28 Eisai Co Ltd Piperidinderivater eller salte deraf og farmaceutiske kompositioner indeholdende forbindelserne
HUT58310A (en) * 1988-12-21 1992-02-28 Upjohn Co Anti-atherosclerotic and anti-thrombotic 1-benzopyran-4-one- and 2-amino-1,3-benzoxazin-4-one derivatives, process for producing them and pharmaceutical compositions containing them
US5278174A (en) * 1990-06-04 1994-01-11 Scios Nova, Inc. Sigma binding site agents
EP0558245A1 (de) * 1992-02-25 1993-09-01 RECORDATI S.A. CHEMICAL and PHARMACEUTICAL COMPANY Heterobicyclische Verbindungen als Alpha-1-Adrenergene und 5HT1A-Rezeptor-Antagonisten

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IL112764A0 (en) 1995-05-26
NO954633L (no) 1995-11-16
AU683549B2 (en) 1997-11-13
WO1995025733A1 (en) 1995-09-28
FI955386A (fi) 1995-11-08
NO954633D0 (no) 1995-11-16
DE69517371T2 (de) 2001-02-22
EP0699197A1 (de) 1996-03-06
JPH08510478A (ja) 1996-11-05
JP3170287B2 (ja) 2001-05-28
FI955386A0 (fi) 1995-11-08
NZ282810A (en) 1996-11-26
NO308001B1 (no) 2000-07-03
PH31442A (en) 1998-11-03
ATE193705T1 (de) 2000-06-15
CA2163251A1 (en) 1995-09-28
PT699197E (pt) 2000-10-31
DK0699197T3 (da) 2000-08-07
US5643927A (en) 1997-07-01
AU2072095A (en) 1995-10-09
GR3034226T3 (en) 2000-12-29
DE69517371D1 (de) 2000-07-13

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